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1 Neuroscience Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 2 Center for Sleep and Respiratory Neurobiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 3 Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 4 Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Submitted 3 October 2002; accepted in final form 7 April 2003
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ABSTRACT |
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and 
isoforms of CREB. Over 24 h, time spent awake was
significantly decreased in CREB mutant mice by approximately
100 min, and time spent in nonrapid eye movement sleep (NREM) sleep was
increased correspondingly. Wake and REM sleep periods were shorter in CREB
mice, and CREB mice had decreased levels of
-activity during wake and REM sleep, consistent with an impairment in
the ability to maintain an activated electroencephalogram. These results
suggest that the CREB protein contributes to the mechanisms by which
wakefulness is maintained and demonstrate that specific genetic alterations in
species as diverse as Drosophila and mice produce similar phenotypes
in arousal and wakefulness. |
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INTRODUCTION |
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). When
phosphorylated, CREB promotes the transcription of a variety of target genes
including zif268 and BDNF (Lonze and Ginty
2002; Mayr and Montminy
2001). Much work has focused on a role for CREB in memory storage
and synaptic plasticity (Silva et al.
1998), and evidence suggests that CREB may play a role in
sleep/wake regulation in mammals as well. Levels of phosphorylated CREB in
cortex are higher during waking than in sleep and are elevated following a
period of sleep deprivation (Cirelli et al.
1996; Cirelli and Tononi
2000a), suggesting that CREB is important for the maintenance of
wakefulness. Afferent input from the locus coeruleus, one of the primary
sources of noradrenaline in the mammalian CNS, has been shown to play a key
role in the phosphorylation of CREB in the cortex
(Cirelli et al. 1996;
Cirelli and Tononi 2000a).
Noradrenergic neurons decrease or cease firing during sleep and are active
during waking (Aston-Jones and Bloom
1981; McCormick et al.
1991), supporting the idea that this neurotransmitter system is
important for wakefulness. Functional data to address the role of CREB in
mammalian sleep/wake regulation, however, is lacking.
Studies in Drosophila have identified CREB as one molecule that
regulates the duration of the rest and active periods in this species
(Hendricks et al. 2001).
Although work in Drosophila has shown that reduced levels of CREB in
this species lead to a reduced duration of the active period
(Hendricks et al. 2001), it is
currently unknown whether mechanisms identified by studies in
Drosophila are relevant to the control of sleep and wakefulness in
mammals. We therefore examined the effects of low levels of CREB on the
regulation of sleep/wake states in mammals. We utilized genetically modified
mice that lack the and isoforms of the CREB protein (CREB
mice; Hummler et al.
1994). These mice have deletion of two of the three major isoforms
of CREB, resulting in the marked reduction of CREB protein levels to 15% of
control levels in all brain regions examined
(Walters and Blendy 2001). The
remaining isoform, CREB
, is incapable of binding to a perfect CRE
consensus site (Walters and Blendy
2001), thus making these mice a useful model for determining if
the CREB protein is involved in the behavioral regulation of sleep/wake
states. We not only studied total amounts of sleep and wake to compare with
results in Drosophila, but also took advantage of the more detailed
phenotyping of sleep available in mice. We examined the effects of this
mutation on sleep state architecture, spectral content of the
electroencephalogram in wakefulness and different sleep states, and the
response to sleep deprivation to assess sleep homeostasis. Our results show
that, as in Drosophila, CREB acts in mammals to promote the duration
of the active state, in this case wakefulness. We further demonstrate that
CREB directly affects the electrophysiological properties of arousal because
CREB-deficient mice have reduced -power in both wakefulness and REM
sleep.
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METHODS |
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To control for effects of genetic background, CREB
homozygous and wild-type mice were obtained from an F1 cross of C57BL/6J and
129/SvEvTac CREB heterozygous mice
(Graves et al. 2002). The CREB
mutation (Hummler et al.
1994) was backcrossed in a heterozygous state for 4–9
generations to 129/SvEvTac mice and 8–13 generations to C57BL/6J mice.
Genotyping was performed by PCR as described
(Walters and Blendy 2001).
Mouse handling
Food and water were provided ad libitum. Mice were maintained on a 12:12 light:dark cycle with lights on at 7 A.M. (ZT 0) and lights off at 7 P.M. (ZT 12). Temperature in the mouse cage was maintained at 25 ± 2°C. All animal care and experiments were carried out in accordance with National Institutes of Health guidelines and were fully approved by the Institutional Animal Care and Use Committee of the University of Pennsylvania.
Surgery
Wild-type (n = 9 female and 8 male mice) and CREB
(n = 8 female and 10 male mice) mice were surgically implanted with
four electroencephalographic (EEG) and two electromyographic (EMG) electrodes.
Surgery was performed as described previously
(Veasey et al. 2000). EEG
electrodes were implanted at 2 mm lateral to Bregma and 1 mm rostral (for 2
rostral EEG electrodes) and 2 mm lateral to Bregma and 3 mm caudal to Bregma
(for 2 caudal EEG electrodes; Veasey et
al. 2000).
Sleep recording
Recordings were performed as described previously
(Veasey et al. 2000), except
EEG signals were filtered at 0.3–35 or at 0.3–300 Hz (1/2
amplitude, 6 dB/octave) and EMG signals were filtered at 1–100 Hz (12A5
amplifier, Astro-Med).
Recording procedures and sleep scoring
Mice were allowed 
9 days of recovery following surgery prior to the
beginning of baseline recordings. Data from 1 day of baseline recording are
presented for each mouse. Mouse records were scored in 10-s epochs as wake,
nonrapid eye movement (NREM), or rapid eye movement (REM) sleep by observation
of the EEG signal and the EMG signal for one baseline day (24 h). After
baseline recording, mice were totally sleep deprived for 6 h from ZT 0 to ZT 6
(Franken et al. 1999). Mice
were sleep deprived by gentle stroking in an attempt to reduce the stress of
the deprivation procedure (Ledoux et al.
1996). Recording was then continued for another 18 h. Sleep-wake
states were scored visually as described
(Veasey et al. 2000) by a
trained observer blind to the genotype of the animal. Waking was defined as a
predominance (within a 10-s epoch) of fast, desynchronized waves and a
high-EMG amplitude. NREM sleep was defined as a predominance of higher
amplitude EEG waves, consistent with either 
- or 
-waveforms,
with a medium EMG signal, and REM sleep was defined as a high-frequency EEG
with a significant predominance of -waves and a very low EMG amplitude
(Veasey et al. 2000). All
values are shown as mean ± SE. Because of loss of signal quality in
some animals after sleep deprivation, the final group sizes for sleep
deprivation analysis were n = 7 female and 7 male wild-type mice and
n = 6 female and 10 male CREB mice. Because no
differences were seen between data from male and female mice, data from these
groups were pooled for all analyses.
Assessment of sleep/wake amounts and microstructure analysis
Percentages of wake, NREM, and REM sleep were calculated in eight 3-h
blocks for the 24-h baseline period. Differences were analyzed with a
mixed-model ANOVA to allow between- and within-group comparisons for main
effects of genotype, time period, condition (baseline or post sleep
deprivation), and their interaction
(Hendricks et al. 2000). A
Bonferroni correction was applied in the post-hoc comparisons.
Sleep microstructure from baseline recordings was characterized by
determining the length of wake bouts, NREM and REM sleep bouts, and total
sleep bouts, as well as the numbers of wake, NREM, REM, and total sleep bouts.
Wake bouts were defined as 30 s of continuous wake; NREM sleep bouts were
defined as 30 s of continuous NREM; REM sleep bouts were defined as 30
s of continuous REM sleep, and total sleep bouts were defined as 30 s of
continuous NREM or REM sleep (Veasey et
al. 2000;
http://rhbase.med.upenn.edu/mouse/sleep/analysis.htm).
All values are shown as mean ± SE. Differences between wild-type and
mutant mice in sleep microstructure for the baseline period were analyzed with
a Student's t-test (Microsoft Excel 2000).
EEG spectral analysis
We performed a fast-Fourier transform (FFT) on the EEG signals over the
24-h baseline period for all subjects recorded with filter settings for EEG
signals set between 0.3 and 35 Hz (n = 7 male and 4 female wild-type
and 4 male and 6 female CREB mice). Overall EEG power spectra
were analyzed by determining the average power in the (1–4 Hz),
(6–8 Hz), and (10–14 Hz) frequency bins
(Franken et al. 1998). The
results obtained from the FFT analysis for wake, NREM, and REM sleep were
normalized as a weighted percentage of total power between 1 and 25 Hz
(Franken et al. 1998). The
mean and SE of the power spectra were determined in each frequency bin for
relative values and differences were analyzed between CREB and
wild-type mice using a Student's t-test (Microsoft Excel 2000).
Differences between CREB and wild-type mice in the time course
of NREM -power rebound after sleep deprivation were analyzed by using a
mixed model ANOVA (Hendricks et al.
2000). Because of loss of signal quality in some animals after
sleep deprivation, the final group sizes for the power analysis after sleep
deprivation were n = 6 male and 3 female wild-type mice and 4 male
and 4 female CREB mice.
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RESULTS |
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We measured levels of wake, NREM, and REM sleep in CREB-deficient and
wild-type mice using EEG and EMG recordings. Over 24 h, CREB
mice had decreased wakefulness compared with their wild-type littermates
(Fig. 1A; 707.9
± 28.5 vs. 594.6 ± 19.3 min for wild-type and CREB
mice, respectively; F[1, 33] = 11.48; P <
0.01). Decreases in wakefulness were accompanied by increases in NREM sleep in
CREB mice (Fig.
1B; 650.0 ± 22.1 vs. 754.1 ± 21.3 min for
wild-type and CREB mice, respectively; F[1, 33] =
10.52; P < 0.01). There was no significant difference in the
amount of REM sleep. Thus the overall change in wakefulness was on the order
of 2 h per day or 16%.
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Both CREB and wild-type mice showed significant changes in
wakefulness and NREM sleep across time (wake: F[7,231] = 32.14;
P < 0.0001; NREM sleep: F[7,231] = 28.12; P <
0.0001), indicating that there were diurnal variations in wake and NREM sleep
levels. The differences between CREB and wild-type mice in
wakefulness and NREM sleep depended on time of day (genotype x time
interaction: wake: F[7,231] = 2.26; P < 0.05; NREM sleep:
F[7,231] = 2.35; P < 0.05). Wild-type and CREB
mice were most different in levels of wake and NREM sleep
during the dark period (Fig.
1). In particular, CREB mice had significantly
increased NREM sleep and decreased wakefulness during the first half of the
dark period, ZT 12–18 (P < 0.01). During this 6-h period,
the reduction in wakefulness was 62 min from a baseline in wild-type mice of
248.1 ± 10.1 min, a difference of 25%. The difference in wakefulness
was most remarkable during the 3-h ZT 15–18 time point, where the
reduction in wakefulness was 39 min, a difference of 32%. REM sleep was not
statistically different between CREB and wild-type mice over 24
h, although there was a trend toward increased REM sleep in the CREB
mice (81.4 ± 5.8 vs. 91.2 ± 6.2 min for wild-type
and CREB mice, respectively; F[1,33] = 1.58;
P > 0.05). A diurnal variation in REM sleep across the day and
night was evident in both mutant and wild-type mice (F[7,213] =
22.53; P < 0.0001) and CREB had significantly more
REM sleep during the ZT 15–18 time point (P < 0.01).
Thus over 24 h CREB mice have almost 2 h of increased NREM
sleep at the expense of wakefulness, mainly during the first half of the dark
period when wild-type mice exhibit maximal levels of wakefulness. These
results suggest that CREB mice exhibit deficits in their
ability to maintain these maximal levels of wakefulness. Generalized motor
impairments could contribute to the reduction in wakefulness. However, open
field activity, home cage activity monitored over 24 h, as well as swim speed,
of CREB mutants was not different from their wild-type
littermates (unpublished data; Graves et
al. 2002), indicating that gross motor ability is not impaired in
CREB mice.
CREB mice have alterations in sleep
microstructure
In addition to altering the overall amount of sleep, a CREB deficiency may
also alter sleep architecture by altering the duration or frequency of sleep
bouts. To determine the nature of the increase in NREM sleep in CREB
mice, we measured the length of each wake, NREM, REM, and total
sleep bout (defined as 30 s or more of wake, NREM, REM, and NREM plus REM
sleep, respectively) as well as the number of wake, NREM, REM, and total sleep
bouts in wild-type and CREB mice. Over the 24-h baseline
period, the average sleep bout length was not altered by the CREB mutation
(data not shown). Because baseline sleep differences were seen mainly during
the dark period, we analyzed sleep microstructure during the light and dark
periods separately. For the light period, when there were no major differences
in the total amounts of wakefulness and sleep, CREB mutants
showed an increase in the number of REM sleep bouts (34.9 ± 2.4 vs.
42.2 ± 0.9 REM bouts for wild-type and CREB mice,
respectively; P < 0.05) but no other significant changes in bout
numbers or length of bouts. During the dark period, when differences in the
total amount of NREM sleep and wakefulness are observed, the number of NREM
sleep bouts was increased in CREB mice
(Fig. 2A; P
< 0.05), as was the number of wake bouts (although this did not reach
statistical significance; Fig.
2A; P = 0.07) and the number of REM bouts
(although this did not quite reach statistical significance;
Fig. 2A; P =
0.052). The length of the average NREM sleep bout did not differ between CREB
and wild-type mice (Fig.
2B), but the length of the average wake bout was
significantly decreased in CREB mice
(Fig. 2B; P
< 0.05), as was the length of the average REM bout
(Fig. 2B; P
< 0.05). These results indicate that increased NREM sleep during the dark
period in CREB mice is accounted for by an increase in the
number of NREM sleep bouts, whereas decreased wakefulness is accounted for by
shorter wake bouts. These results also indicate that CREB mice
are not able to maintain a cortical activated state (i.e., wakefulness and REM
sleep) for the same amount of time as can wild-type mice.
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CREB-deficient mice exhibit decreased -power
Different sleep/wake states are characterized by prominent frequencies in
the EEG spectrum. To examine differences in the EEG power spectrum between
CREB and wild-type mice, we performed a FFT analysis on the
baseline 24 h to calculate the power (µV2; 1 to 25 Hz) of the
EEG signal for each subject. There was no detectable difference in the total
(1 to 25 Hz) EEG power between CREB and wild-type mice (3241
± 824 and 2390 ± 1017 µV2 for wild-type and CREB
mice, respectively; P > 0.05), although this may be
due to variability in these measures of absolute spectral power. Because of
this, we determined relative power by expressing the spectral power in wake,
NREM, and REM sleep as a weighted percentage of total power between 1 and 25
Hz (Franken et al. 1998). This
analysis indicated that CREB mice had a decrease in the level
of -power during wake (Fig.
3A) and REM sleep
(Fig. 3C) and a
decrease in the level of power during REM sleep
(Fig. 3C) compared
with wild-type mice.
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Response to sleep deprivation in CREB-deficient mice
To examine the homeostatic response to sleep deprivation
(Borbely 1982), CREB
and wild-type mice were totally sleep deprived for 6 h,
starting at ZT 0, using the technique of gentle handling
(Franken et al. 1999;
Ledoux et al. 1996). Over the
18 h after the end of sleep deprivation (ZT 6–24) and during the light
and dark periods examined separately, the mixed model ANOVA showed that there
were no overall differences between CREB mice and wild-type
mice in wake, NREM, or REM sleep as a result of sleep deprivation (wake:
F[1,28] = 2.41; NREM: F[1,28] = 1.39; REM: F[1,28]
= 2.04; P's > 0.05; Fig.
4). The effectiveness of the sleep deprivation period was
evaluated and found to be similar in CREB and wild-type mice in
that both had increases in NREM sleep -power that declined over the
18-h post sleep-deprivation period (F[5,15] = 3.02; P <
0.05; data not shown). Despite these overall similarities in the responses of
CREB and wild-type mice to 6 h of sleep deprivation, CREB
mice had significantly more NREM and REM sleep rebound and a
corresponding decrease in wakefulness during the first 3 h of the dark period
after sleep deprivation (ZT 12–15; wake rebound: –9.0 ± 6.9
vs. –18.5 ± 5.76 min for wild-type and CREB mice;
NREM sleep rebound: 6.1 ± 6.1 vs. 12.1 ± 5.35 min for wild-type
and CREB mice, respectively; REM sleep rebound: 3.0 ±
1.2 vs. 6.5 ± 1.0 min for wild-type and CREB mice,
respectively; Fig. 4;
P's < 0.01). These results show that CREB and
wild-type mice both possess a sleep homeostatic response. However, the larger
differences we found in the baseline amounts of NREM sleep and wakefulness are
not reflected in similar differences in the homeostatic response to sleep
deprivation. The differences after sleep deprivation are temporally limited
and are largest at the start of the dark period when baseline differences were
greatest.
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DISCUSSION |
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),
supporting the idea that conserved molecular mechanisms underlie these
phenotypes. Moreover, because more detailed phenotyping of state with
electroencephalographic recording is possible in mice, we were able to extend
these observations. Specifically, we found that the decrease in wakefulness
was largely due to an inability of CREB mutant mice to maintain longer periods
of wakefulness during the nocturnal active period. We also found that the
electrophysiological properties of wakefulness, as well as REM sleep, were
different in the CREB mutant mice as compared with wild-type mice, with the
mutants having less -power in these states. These observations support
the hypothesis that CREB regulates the expression of genes that encode
proteins that act to maintain cortical arousal.
To address our hypothesis, we used mutant mice that lack the and
isoforms of CREB (Hummler et al.
1994). Although in rats it is known that CREB is activated by
phosphorylation in cortical brain regions during wakefulness
(Cirelli et al. 1996;
Cirelli and Tononi 2000a),
studies in other brain regions, particularly those more directly involved in
sleep/wake regulation, have not yet been performed. To this end, we used
mutant mice with globally decreased levels of CREB to create a study that was
sensitive to changes in brain nuclei that are otherwise not experimentally
accessible.
The most likely interpretation of our data, along with those in
Drosophila, is that the activation of CREB, through phosphorylation
via the cAMP/PKA/CREB signaling pathway
(Abel et al. 1997;
Hendricks et al. 2001;
Ogasahara et al. 1981), is
important for the maintenance of wakefulness. This activation of CREB is
perhaps in response to one of the wake-active neurotransmitters
(noradrenaline, serotonin, orexin, histamine, and acetylcholine;
McGinty and Szymusiak 2000).
There is specific evidence to support a role for noradrenaline. Unilateral
neurotoxic lesions of the locus coeruleus in rats markedly reduces the levels
of phosphorylated CREB in ipsilateral cortical neurons during wakefulness as
compared with the contralateral side
(Cirelli et al. 1996). Because
the recently discovered orexin/hypocretin system has been shown to have
extensive neural connections with many arousal-promoting areas, including the
locus coeruleus (Aston-Jones et al.
2001; Sutcliffe and De Lecea
2002), one possibility is that the locus coeruleus, after input
from the orexin/hypocretin system, influences cortical or wake-promoting
neuronal groups through activation of the cAMP/PKA/CREB signaling pathway
(Fig. 5). In turn, after
phosphorylation, CREB may induce the expression of genes that help sustain
wakefulness (Cirelli and Tononi
2000a). Studies showing that levels of phosphorylated CREB are
increased after extended wakefulness
(Cirelli and Tonini 2000a),
coupled with our results, support the idea that phosphorylated CREB is needed
to maintain extended wakefulness, rather than being part of sleep-promoting
machinery. Although our results show that CREB plays an important role in the
regulation of wakefulness, we do not know where CREB acts nor do we know the
downstream genes that are involved.
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Our model (Fig. 5) suggests
that CREB acts downstream from norepinephrine to regulate wakefulness. It is
difficult, however, to attribute these actions directly to CREB because the
genetic alteration of CREB may act developmentally to alter the expression of
other molecules involved in regulating wakefulness. To address this issue, we
have begun molecular and neurochemical studies in the CREB
mice. In our preliminary microarray studies examining change in gene
expression in the cerebral cortex of CREB mice, we did not
observe changes in the expression levels of genes encoding enzymes involved in
the synthesis of wake-active neurotransmitters or their receptors (M.
Mackiewicz, K. Hellman, J. A. Blendy, T. Abel, and A. Pack, unpublished data).
Neurochemical studies have revealed that levels of norepinephrine measured
using HPLC are not altered in the cerebral cortex of CREB mice
(wild-type mice: 1060 ± 79 ng norepinephrine/g tissue, n = 3;
CREB mice: 1275 ± 203 ng norepinephrine/g tissue,
n = 4). Further, anatomical alterations and alterations in
c-fos staining have not been observed in the CREB
mutant mice on a B6/129 F1 hybrid background (J. A. Blendy, unpublished
observations). Thus our data are consistent with the idea that CREB acts
downstream of norepinephrine to regulate wakefulness, and these observations
may have applicability to human sleep disorders in which CREB function may be
dysregulated. Future studies with mice that lack norepinephrine as well as
mice in which CREB activity is conditionally regulated will be needed.
CREB may mediate the maintenance of cortical arousal by acting in the
cortex as well as in one of the wake-active nuclei, including the brain stem
serotonergic and noradrenergic nuclei, histaminergic nuclei within the
hypothalamus, and potentially the amygdala
(Charifi et al. 2000;
McGinty and Szymusiak 2000).
Behavioral studies of CREB mice suggest that CREB may be
particularly important for amygdaloid function, because CREB
mice are impaired in contextual and cued fear conditioning
(Bourtchouladze et al. 1994;
Gass et al. 1998;
Graves et al. 2002;
Kogan et al. 1997), which are
both amygdala-dependent tasks (Phillips
and LeDoux 1992). In terms of sleep/wake regulation, alterations
in amygdala function result in increased NREM sleep
(Charifi et al. 2000), and
shorter REM sleep episodes (Cheng et al.
1998; Morrison et al.
2000; Sanford et al.
1995), as observed in the CREB mice. It seems
unlikely, however, that this is the only area where CREB is playing a role.
CREB-deficient mice have, as described above, reduced -power in
wakefulness and REM sleep. Because -rhythm originates from the
hippocampus (Vanderwolf et al.
1977), this finding may reflect differences in hippocampal
function in CREB-deficient mice as measured behaviorally by water maze
performance and electrophysiologically by studies of place cells
(Bourtchouladze et al. 1994;
Cho et al. 1998;
Kogan et al. 1997).
An interesting observation from our studies is that although we saw major
differences between the amounts of wakefulness and sleep in the dark period,
there were minimal differences in the sleep homeostatic response to sleep
deprivation between wild-type and mutant mice. One possibility is that longer
periods of sleep deprivation will be needed to observe large differences.
Alternatively, the recovery response to sleep deprivation might involve
different molecular mechanisms than those regulating baseline levels of sleep
and wakefulness. We found that the altered response to sleep deprivation in
CREB mice is specific to normally occurring peak levels of
arousal during the active period, further supporting the idea that CREB is
needed to maintain peak levels of arousal.
Circadian processes have also been proposed to play a role in regulating
the sleep/wake cycle (Borbely
1982; Edgar et al.
1993). We found that the diurnal variation in sleep/wake cycles
was not altered in CREB mutants. Also, CREB and
wild-type mice do not differ in their circadian periods measured with
wheel-running activity in constant darkness or in their ability to entrain to
a light:dark cycle (data not shown). Although CREB has also been implicated in
the response to phase-shifting light pulses
(Ding et al. 1997;
Gau et al. 2002), such
alterations are unlikely to explain our findings of altered sleep/wake states
during the dark period in the absence of external light pulses. Thus the
alterations in wakefulness in CREB mutant mice that we report seem unlikely to
arise from altered circadian processes.
Current models of sleep/wake regulation are generally based on the concept
that there are sleep-promoting mechanisms that increase in intensity with
increased duration of prior wakefulness
(Borbely 1982). Our data,
together with that from Drosophila
(Hendricks et al. 2001),
indicate that there are, in addition, molecular mechanisms that promote
wakefulness that are activated by neurotransmitters such as noradrenaline.
Compatible with this new concept is the observation that there are many genes
upregulated during wakefulness (Cirelli and Tononi
2000a,b).
Such wake-promoting mechanisms will need, in time, to be incorporated into new
models of sleep/wake regulation.
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DISCLOSURES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests: T. Abel, Department of Biology, University of Pennsylvania, 38th Street and Hamilton Walk, 319 Leidy Labs, Philadelphia, PA 19104 (E-mail: abele{at}sas.upenn.edu).
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